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Role of endocytosis in cellular uptake of sex steroids Hammes A, et al .
Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.
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Dynamic changes in leptin distribution in the progression from ovum to blastocyst of the pre-implantation mouse embryo. Schulz LC et al. The hormone leptin, which is primarily produced by adipose tissue, is a critical permissive factor for multiple reproductive events in the mouse, including implantation. In the CD1 strain, maternally-derived leptin from the oocyte becomes differentially distributed among blastomeres of pre-implantation embryos to create a polarized pattern, a feature consistent with a model of development in which blastomeres are biased towards a particular fate as early as the 2-cell stage. Here, we have confirmed that embryonic leptin is of maternal origin and re-examined leptin distribution in two distinct strains in which embryos were derived after either normal ovulation or superovulation. A polarized pattern of leptin distribution was found in the majority of both CD1 and CF1 embryos (79.1 % and 76.9 %, respectively) collected following superovulation, but was reduced, particularly in CF1 embryos (29.8 %; p < 0.0001), after natural ovulation. The difference in leptin asymmetries in the CF1 strain arose between ovulation and the first cleavage division, and was not affected by removal of the zona pellucida. Presence or absence of leptin polarization was not linked to differences in ability of embryos to develop normally to blastocyst. In the early blastocyst, leptin was confined subcortically to trophectoderm but upon blastocoel expansion it was lost from cells. Throughout development leptin co-localized with LRP2, a multi-ligand transport protein, and its patterning resembled that noted for the maternal-effect proteins OOEP, NLRP5, and PADI6, suggesting that it is a component of the subcortical maternal complex with as yet unknown significance in pre-implantation development.
This gene was found in a mouse DNA array analysis of transcripts expressed in mouse preovulatory follicles.
Zheng et al investigated immunohistochemically the distribution in rats of the homologous proteins gp330 and the LDL receptor-related protein (LRP/alpha 2MR), and a receptor-associated protein (RAP), and the sites to which soluble exogenous RAP binds. We found gp330 in a restricted group of epithelial cells, including renal proximal tubule cells, podocytes, Type II pneumocytes, cells of the parathyroid, thyroid, epididymis, lining of the uterus, ependyma, retina, ciliary body, yolk sac, and placenta. In these cells gp330 was detected mainly at the cell surface, except for parathyroid and retinal epithelial cells, where diffuse cell staining was found. LRP/alpha 2MR was widely distributed in interstitial cells, notably in fibroblasts and macrophages, and was also present in a selected group of epithelial or specialized cells, including hepatocytes, adrenal cortical cells, follicular cells of the ovary, cells of the choroid plexus, ciliary body, mesangial cells, and some neurons. In certain cells, notably hepatocytes and adrenal cortical cells, LRP/alpha 2MR was detected mainly on the surface, but in others, including macrophages, fibroblasts, and epithelial cells of the choroid plexus and ciliary body, staining throughout the cell was seen. The only cells that clearly expressed both LRP/alpha 2MR and gp330 were retinal and ciliary epithelial cells. RAP was found in intracellular vesicles in all cells that expressed gp330 or LRP/alpha 2MR. RAP was not definitely detected on the cell surface. Binding sites for RAP were found on the surface of those cells with surface gp330 or LRP, and also throughout the cytoplasm in cells with diffuse cellular LRP/alpha 2MR or gp330. Because of their different locations, we conclude that gp330 and LRP/alpha 2MR serve distinct functions in vivo, despite similarities in ligand-binding properties observed in vitro. Since RAP is found largely within cells, its major physiological function may be concerned with intracellular assembly or trafficking of the receptors to which it binds.
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